Fluorinated steroids



United States Patent 3,257,424 FLUORINATED STEROIDS John S. Tadanier,Chicago, and John Wayne Cole, Deer- This application is acontinuation-in-part of our earlier filed application, Serial No.167,413, filed January 19, 1962, now abandoned.

The present invention relates to a new group of steroids, Moreparticularly, it relates to a new series of fluorinated androstanes andpregnanes.

According to the present invention, compounds of the structure (I) areprovided wherein the A-ring has a structure selected from the partialstructures- F and 0- o= F on oooand wherein R is :0,

v F COCH OCOCHE with the further provision that the compound contains atactivities as androgen-antiandrogens. This kind of activity has beendescribed in more detail by Dorfman and Dorfman in Acta Endocrinologica,volume 33, page 3-08 (1960) and can be observed by endocrine assays inWarmblooded animals. The novel compounds, when used in therapy, can beadministered in a wide variety of oral or parenteral dosage forms,singly or in admixture with other active compounds. They can beassociatedwith a pharmaceutical carrier which may be solid or liquid.Solid compositions can be processed into tablets, powders, capsules orthe like, and the liquid compositions may be solutions, dispersions,suspensions, emulsions or elixirs.

For the preparationof the above-described new compounds, a steroid ofthe formula wherein Ris =0,

and R is =0 or is dissolved in an inert, non-aqueous solvent such aschloroform and mixed with sulfur tetrafluoride in the presence of acatalytic amount of boron trifluoride or hydrogen fluoride. Borontrifiuoride can be replaced by. other Lewis acids, producing similarresults. When hydrogen fluoride is intended to be used as the catalyst,it may be added directlyas such or, alternatively, it may be formed insitu by the addition of a small amount of a hydroxy compound, e.g.'water, methanol, ethanol, isopropanol, phenol, etc. to the reactionmixture. When boron trifluoride or other Lewis acids are used, they areadded directly to the reaction mixture.

The desired reaction takes place slowly at low temperatures and rapidlyat more elevated temperatures. We have found that about 40 C. is asuitable temperature for the formation of the new gem-difiuoro steroids;a prac tical temperature range for the above-described reaction isbetween about 0 and about 60 C. Under these conditions a keto-group inthe C-ring remains substantially unaffected, while keto-groups in the3-, 17-, or 20-position react to the corresponding gem-difluorostructures.

The above reference to inert, non-aqueous solvents as the reactionmedium is used to express that the solvent is chosen in such a mannerthat it will not react with any of the reactants or the formedgem-difluorosteroid in the reaction mixture. As explained above,compounds containing a hydroxy group are therefore excluded by this termsince such solvents react with sulfur tetrafluoride. Solvents suitablefor the present reaction are carbon tetrachloride, chloroform, ether,methylene chloride, benzene and other saturated or aromatic liquids freeof hydroxyand keto-groups.

Where the starting material of Formula II contains ketogroups in the 3-and 17-position, both these keto-groups are replaceable by thegem-difluoro substituent without affecting the ket'o-group at 11 or 12to any appreciable extent. The same holds true if the l7-position of thesteroid carries a substituent which includes a keto-group, as forinstance in the case of pregnan-3,1l,20-triones. Where the startingmaterial contains only one other ketogroup aside from that in the 11- or12-position, e.g., in l7-acetoxyandrostane-3,ll-dione, in3-acetoxyandrostane- 12,17-dione, or in B-acetoxypregnane-l1,20-dione,only one keto-group undergoes the above conversion, again without anyappreciable reaction taking place in the 11- or 12-position.

A detailed description of the production of the new compounds is foundin the following examples, which are meant to be illustrations only anddo not constitute the only embodiments of the present invention.

EXAMPLE 1 3,3,20,20-tetraflumrO-Sa-pregnan-Z 1 -one A solution of 3grams of 5a-pregnane-3,11,20-trione in 30 ml. of chloroform containing3% ethanol is heated to 40 C, for 15 hours with 14 grams of sulfurtetrafluoride. After removal of the excess sulfur tetrafluoride byevaporation the product is worked up by separating it with chloroformand water. The combined chloroform solutions are chromatographed onneutral alumina of activity 111. The alumina column is then eluted withbenzene/ Skellysolve B (1:10) (Skellysolve B is a petroleum etherfraction boiling at 6080), yielding 1545 mg. of crystalline materialfrom which 290 mg. of pure 3,3,20,20-tetrafiuoro-5a-pregnan-11-onemelting at 1701 C. is obtained after recrystallization frombenzene/Skellysolve B (1:10). The new compound analyzes 66.83% C, 7.90%H, and 19.94% P, which corresponds with the calculated values for C H OFIn a modification of this example, the above chloroform is replaced withmethylene chloride to which 0.3 gram of boron trifluon'de is added ascatalyst. Substantially the same result is obtained after the work-updescribed above.

EXAMPLE 2.

Further elution of the above alumina column with benzene/Skellysolve B(1:5) yields 1.36 grams of crystalline material from which 890 mg. ofpure 3,3-dlfillOIO-5ozpregnane-ltLZO-dione melting at 1556 C. isobtained after recrystallization from benzene/Skellysolve B (1:5). Theanalysis of this product shows 71.81% C, 8.36% H, and 10.63% F,corresponding With the calculated values for C21H3QO2F2- EXAMPLE 33,3,20,20-tetraflur0-5 -pregnqn-11-one A solution of 2 grams ofSfl-pregnane-SJ1,20-trione in 20 ml. of chloroform containing 3% ethanolis heated for 15 hours at 40? C. with 10 grams of sulfur tetrafiuoride.After evaporation, the residue is extracted with chloroform and waterand the chloroform solution is absorbed on neutral alumina in achromatography column. Elution with benzene/Skellysolve B (1:10) yields168 mg. of white crystalline material melting at l624 C.Recrystallization of this material produces 122 mg. Olf pure3,3,20,20-tetrafluoro-Sfi-pregnan-1l-one melting at 167-8 C., by usingbenzene/Skellysolve B (1:10) asthe recrystallization medium. Ananalytical sample of this product shows 67.58% C, 8.03% H, and 20.77% F,corresponding with the calculated values for C H OF Analogous resultsare obtained by replacing Skellysolve B in this example with hexane.

EXAMPLE 4 3,3-diflu0r0-5-pregnane-11,20-di0ne By further elution of thealumina column of the previous example with benzene/Skellysolve B (1:1),603 mg. of a crystalline solid is obtained, melting at l339 C.Recrystallization of this material with benzene/Skellysolve B (1:1)yields 391 mg. of pure 3,3-difluoro-5B- pregnane-ll,20-dione. Ananalytical sample shows 71.84% C, 8.61% H, and 10.87% F, correspondingwith calculated values for C H O F EXAMPLE 5 3,3,1 7 ,1 7 -tetraflu0ro-5a-androstan-l 1 -one A solution of 2.1 grams of5a-androstane-3,11,17-trione in 20 ml. of chl'orofiorm containing 1%hydrogen fluoride is heated at 40 C. in a stainless steel pressurecylinder with 10.6 grams of sulfur tetrafluoride for 15 hours. Thegaseous products are removed thereafter and the residue is washed into aSOD-ml. separatory funnel with five SO-ml. portions of chloroform. Theresulting chloroform solution is Washed With two 100-ml. portions ofWater, 100-ml. of 5% sodium bicarbonate solution, and finally with two100-ml. portions of Water. The chloroform solution is then dried overanhydrous magnesium sulfate and concentrated under partial vacuum on asteam bath, leaving a dark brown residue. This material is extractedwith two portions of 200 ml. each of boiling ethanol, and the combinedextracts are subsequently treated with carbon3,3-diflu0r0-5a-androstane-l1,17-di0ne The alumina column used in thechromatogram of Example 5 is further eluted with benzene from whichsolution, after the usual work-up,3,3-difluoro-5.a-androstane-ll,l7-dione is obtained as white crystals.The analytical values correspond with the empirical formula 19 2s 2 2-EXAMPLE 7 3,3,1 7,] 7-tetrafluoro-Sfi-androstan-I1-0ne By following theprocedure outlined in Example 5,

5,B-androstane-3,l1,17-trione is fluorinated to produce3,3,17,17-tetrafluoro-5B-androstan-1l-0ne by elution of the aluminacolumn with benzene/hexane (1:10).

EXAMPLE 8 3,3,diflu0ro-5B-androstane-I 1,1 7-di0ne After elution of the3,3,17,l7-tetrafluoro-55-androstan- 1*1-one according to Example 7, thealumina column is further eluted with benzene from which3,3-difluoro-5flandrostane-11,17-dione is recovered upon evaporation ofthe solvent.

EXAMPLE 9 A mixture of 2.2 grams of androst-4-ene-3,l1,17-trione, 8.0grams of sulfur tetrafiuoride, 0.4 gram of boron trifluoride, and 20 ml.of ethanol-free chloroform is heated for 10 hours in an autoclave at 40C. The reaction mixture is allowed to cool to room temperature and thegaseous products are stripped. The residue is washed into a 5004ml.separatory funnel with six 50-ml. portions of chloroform. The blackresinous byproduct is discarded. The chloroform solution is twice washedwith 100-ml. portions of water, and subsequently with 100-ml. of 5%sodiumbicarbonate and finally with two 100-ml. portions of water. Thechloroform solution is dried over anhydrous magnesium sulfate and thechloroform is stripped under partial vacuum on a steam bath to leave adark crystalline residue. This material is heated with ml. of boilingethanol, decolorized with carbon, and filtered through Celite. Thecarbon/Celite mat is washed with three 25-ml. portions of boilingethanol and the washings are added to the original ethanol filtrate. Theethanol is stripped under partial vacuum in the steam bath leaving abrown precipitate. This material is chromatographed on 70 grams ofalumina and eluted with benzene/ hexane (1:1), yielding a crystallinesolid upon evaporation of the solution. Recrystallization from ethanol/water produces 17,17-difluoroandrost-4-ene-3,1l-dione. The analysiscorresponds to the calculated values for C19H24O2F2 EXAMPLE 10 Uponhydrogenation of 17,17-difluoroaudrost-4-ene- 3,11-dione of Example 9 inthe presence of palladium catalyst according to the method described bySteiger and Reichstein in Helv. Chem. Acta, volume 20, pages 822 ff.(1937), a good yield of 17,l7-difluoro-5u-androstane- 3,11-dione isobtained.

Elution with benzene/hexane (1:10)

5 EXAMPLE 11 By substituting the androst-4-ene-3,11,17-trione in Example9 with pregn-4-ene-3,11,20-trione, but otherwise following the procedurein Example 9, 20,20-difiuoropregn-4-ene-3,11-dione is obtained. Theanalysis is in agreement with the calculated values for the empiricalformula C21H2302F2.

EXAMPLE 12 20,2 O-di fluoro-S oi-pregnane-3 ,1 1 -dine By hydrogenating20,20-difiuoropregn-4-ene-3,1l-dione in the presence of palladiumcatalyst according to Example 10, a good yield of20,20-difluoro-a-pregnane-3,11- dione is obtained. The analysis is inagreement with the calculated values for C H O F From the reaction of 173-acetoxy-S/SGandrOstane-B,11- dione with sulfur tetrafluoride under theconditions described in Example 3, followed by elution of the aluminacolumn with benzene/Skellysolve B (1:1) and evaporation of the eluate,17fi-acetoxy-3,3-difluoro-5/3-androstanll-one is obtained. Theanalytical values obtained are in agreement with the compound of theempirical formula 02 11301 203- EXAMPLE 14 By substituting3a-acetoxy-5fi-pregnan-11,20-dione for the androst-4-ene-3,11,17-trionein Example 9, 3a-acetoxy- 20,20-ditluoro-5p-pregnan-1l-one of theformula 2s a4 2 s is obtained.

EXAMPLE The 3u-acetoxy-20,20-difluoro-Sfl-pregnan-1l-one of Example 14is hydrolyzed with 2% potassium hydroxide in methanol, followed byevaporation and water-washing the residue to obtain3a-hydroxy-20,20-difluoro-5B-pregnan-ll-one. Oxidation with chromic acidin acetic acid solution at room temperature for four hours, and additionof water to precipitate the product, yields 20,20-difluoro-5fl-pregnane-3,11-dione of the formula C H F O By mixing 1 part of3a-acetoxy-S/i-androstane-11,17- dione with 10 parts of ethanol-freechloroform, 4 parts of sulfur tetrafiuoride, and 0.2 part of borontrifluoride, and treating the mixture as described in Example 9,311-2166- toxy-17,17-difluoro-5fi-androstan-11 one of the empiricalformula C H F O is obtained.

EXAMPLE 17 3,3,17,17-tetrafluor0-5a-andr0stan-12-0ne By further elutingthe alumina column used in the chromatogram of Example 17 with benzene,3,3-difluoro- 5a-androstane-12,17-dione is obtained as white crystals.The analytical values correspond with those calculated for the empiricalformula C H O F EXAMPLE 19 3,3,2 0,20-tetrafluoro-5,B-pregnan-1 2-0ne Byfollowing the procedure shown in Example 3 but using5fl-pregnane-3,12,20-trione as the starting material (described byWagner et al., I.A.C.S. 71, 3856, of 1949),3,3,20,ZO-tetrafluoro-SB-pregnan-12-one is obtained in pure form byrecrystallization of the crude material obtained according to Example 3.

The corresponding Sat-isomer is obtained in the same fashion by using5a-pregnane-3,12,20-trione (described by Wagner et a1. ibid).

EXAMPLE 20 3,3-diflu0ro-5fi-pregnane-12,20-dione By further elution ofthe alumina column of the previous example with benzene/Skellysolve B(1:1), a crystalline solid is obtained which can be crystallized fromthe same solvent mixture to produce an analytical sample of3,3-difluoro-5B-pregnane-12,20-dione of which the analytical valuescorrespond with those calculated for the compound of empirical formula CH O F It will be seen from the above examples that the workup of thedesired compounds always includes exposure thereof to water which hasthe effect of breaking and dissolving any remaining Lewis-acidcomplexes.

In all the above examples, the assigned structures are found to agreewith the ultraviolet and infrared spectra expected for such compounds.The melting points were all determined in a Fisher-Johns melting pointapparatus.

Others may practice the invention in any of the nurnerous ways whichwill be suggested to one skilled in the art by the present disclosure.All such practice of the invention is considered a part hereof providedit falls within the scope of the appended claims.

We claim:

1. Gem-difluorosteroids of the formula wherein the A-ring has a partialstructure selected from the group consisting of and wherein R isselected from the group consisting of 7 OCOCH; OOCH CF CH and wherein atleast one of the substituents R and R includes fluorine.

2. 3,3,20,20-tetrafluerode-pregnan-1l-one.

3. 3,3-difluoro-5u-pregnane-11,20-dione.

4. 3,3,20,20-tetrafiuoro-Set-pregnan-11-one.

5. 3,3-difiuoro-5B-pregnane-11,20-dione.

No references cited.

LEWIS GOTTS, Primary Examiner.

ELBERT L. ROBERTS, Examiner.

1. GEM-DIFLUOROSTEROIDS OF THE FORMULA